204 research outputs found
HYDROXY-DIRECTED FLUORINATION OF REMOTE UNACTIVATED C(sp3)-H BONDS: A NEW AGE OF DIASTEREOSELECTIVE RADICAL FLUORINATION
No full textAfter years of research with Dr. Lectka and fellow students, we report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3’-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with 19F-1H HOESY experiments, calculations, and more
Directed Fluorination and the Functionalization of Selectfluor Radical Dication
No full textFluorine has long been an element of peculiar interest to the scientific community at large. From the role it plays in pharmaceuticals to forever chemicals, fluorine has had a profound impact in the world at large. Yet, despite all of these uses and potential, many aspects of fluorine chemistry remain shrouded in mystery, particularly pertaining to aliphatic fluorines. Over the past few years our lab has focused on the idea of directed radical fluorination in order to achieve a mild, selective fluorination of sp3 carbons. Previously this idea was used to achieve fluorination on activated benzylic sites, and highly symmetric substrates. Further work eventually opened the door for carbonyls to direct fluorination on completely unactivated C-H bonds using hydrogen bonding to achieve a highly selective product. Herein, we report further advancements, wherein hydroxy, and pyridyl groups are shown to direct fluorination. Additionally, we report the use of an electrochemically initiated system to provide an alternate pathway to achieve these reactions. Finally, we demonstrate the various unique reactivities of primary epoxides with Selectfluor Radical Dication (SRD). All in all, this assortment of new schemes and pathways to achieve selective fluorination aims to further push the notion that radical based fluorination is a valuable tool in the realm of late-stage functionalization
From H to F: Strategies in Selective sp3 C-H Fluorination
No full textThe replacement of a single hydrogen atom by fluorine can impart a unique set of chemical and physical properties onto organic molecules, oftentimes modifying their reactivity. In many instances, fluorination improves the metabolic stability of pharmaceuticals, amplifies the electronic properties of polymers, and heightens the efficiency of industrial solvents and surfactants. Despite these and others, fluorination methods have endeavored to become commonplace, a fact consistent with the lack of synthetically mild sources of atomic fluorine. Until recently, fluorination strategies have been predicated upon the use of harsh, unselective, and often destructive sources of fluorine, such as fluorine gas and explosive hypofluorites, limiting their synthetic utility.
Over the last 20 years, the advent of bench-top stable N-F reagents have incurred a renaissance in the discovery of regio- and chemoselective methods for the direct incorporation of fluorine atoms into organic molecules. In this Dissertation, the applications of one such N-F compound, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) is highlighted as a practical reagent for the monofluorination of unactivated sp3 C-H bonds of aliphatic, benzylic, and allylic containing compounds in conjunction with earth-abundant, inexpensive transition metals and commercially available photocatalysts. The use of Selectfluor in the α,α-difluorination of acid chloride derivatives and photocatalyzed ring opening-β-fluorination of cyclopropanols is likewise discussed. Mechanistic evidence suggests the involvement of putative carbon-centered radicals (or radical ions) during fluorination with Selectfluor acting as a versatile fluorine atom transfer reagent
Directed Fluorination and the Functionalization of Selectfluor Radical Dication
No full textFluorine has long been an element of peculiar interest to the scientific community at large. From the role it plays in pharmaceuticals to forever chemicals, fluorine has had a profound impact in the world at large. Yet, despite all of these uses and potential, many aspects of fluorine chemistry remain shrouded in mystery, particularly pertaining to aliphatic fluorines. Over the past few years our lab has focused on the idea of directed radical fluorination in order to achieve a mild, selective fluorination of sp3 carbons. Previously this idea was used to achieve fluorination on activated benzylic sites, and highly symmetric substrates. Further work eventually opened the door for carbonyls to direct fluorination on completely unactivated C-H bonds using hydrogen bonding to achieve a highly selective product. Herein, we report further advancements, wherein hydroxy, and pyridyl groups are shown to direct fluorination. Additionally, we report the use of an electrochemically initiated system to provide an alternate pathway to achieve these reactions. Finally, we demonstrate the various unique reactivities of primary epoxides with Selectfluor Radical Dication (SRD). All in all, this assortment of new schemes and pathways to achieve selective fluorination aims to further push the notion that radical based fluorination is a valuable tool in the realm of late-stage functionalization
A New Dimension in Fluorine Chemistry: Fluorine in Close Interactions
No full textThis work attempts to shed some light on some of the fundamental chemistry utilized by C-F bonds in organofluorine compounds, with special care to noncovalent interactions. A fluorinated sesquinorbornane scaffold was the template for the majority of the studies owing to its rigid conformation and ability to be modified. Thanks to those two attributes, the properties of C-F bonds were observed under various conditions in a multitude of different conformations. Through that work, the C-F bond was observed to take part in SN1 reactions through anchimeric assistance. Even more interesting is the anchimeric assistance is facilitated through a positively charged fluoronium intermediate. In addition, the conformation of the scaffold, allows other functional groups to be placed in close proximity to the C-F bond. After making a series of molecules with different functional groups, the through-space interaction of the C-F bond with the proximal C-H was investigated. A correlation between proton-fluorine coupling constants and the interaction’s strength was observed. The positioning also allowed the observation of a strong hydrogen bonding interaction between the fluorine and an alcohol. While the hydrogen bond appears strong by most spectroscopic methods, IR spectroscopy shows little to no shift when compared to a control molecule. This appears to be a rare case of bond compression from steric strain cancelling out bond relaxation from hydrogen bonding, a so called “no-shift” bond. In an attempt to be sure our system can be used to generate hydrogen bonds, a hydrogen bond between an alcohol and a nonconjugated pi-system was investigated. Owing to the reduction of steric strain in the molecule a strong hydrogen bond was observed accompanied by a characteristic red shift in the IR spectrum. Interestingly the red shift was nearly 189 cm-1, which is much larger than other observed examples of this type of interaction. In order to bolster our claims about a fluoronium ion intermediate, an in depth investigation into the reactivity of the fluoronium system was reported. This was done through several rate studies, control reactions and isotopic labeling experiments. All of which indicate that the fluoronium is the most likely intermediate. Finally another example of fluorine acting as a directing group was investigated. Specifically, a C-F bond was found to influence a Diels-Alder reaction between a fluorinated dienophile and a borole so that one product was favored to a substantial degree
THE GENESIS AND EVOLUTION OF DIRECTED C(SP3)-H RADICAL FLUORINATION
No full textFluoroorganic molecules have become indispensable in medicinal chemistry, materials science, and biology. Despite all of the applications in many fields of chemistry, accessibility of most fluorinated compounds is limited, especially organic molecules containing aliphatic fluorides. One would ideally like to access the aliphatic fluorides through direct functionalization of sp3 C–H bonds (via radical based routes)–this would open limitless possibilities to synthesize a variety of fluorinated molecules. Lately, our laboratory and others accomplished a notable improvement in controlling the reactivity of aliphatic C–H bonds towards radical based fluorinations but had only demonstrated selective sp3 C–H bond fluorination on highly symmetric substrates or those containing more activated benzylic C–H bonds. The next step of progression would be to direct radical fluorination in complex natural products. We envisioned two approaches to accomplish this task through directed sp3 C–H bond functionalization. Accordingly, herein, directed fluorination methods, and advances in selectivity in functionalizing terpenoids and other complex organic molecules using either carbonyl or hydroxy groups to target unactivated C–H bonds are discussed. These strategies have helped radical based fluorination reactions become a valuable synthetic approach to functionalize complex moieties through late-stage fluorination
INVESTIGATIONS OF MONOBACTAM BIOSYNTHESIS AND CARBAPENEM SYNTHASE ENGINEERING
No full textZinc metallo-β-lactamases, although long known, have only recently emerged in the clinic to confer potent resistance to penicillins, cephalosporins and even carbapenems, the β-lactam antibiotics of last resort in human medicine. The monobactams, however, having structurally distinct N-sulfonated monocyclic β-lactam rings are resistant to these enzymes and are the most effective class to combat e.g. carbapenem-resistant enterobacteria (CRE). Here we report unprecedented non-ribosomal peptide synthetase activities where an assembled tripeptide is N-sulfonated in trans prior to direct synthesis of the N-sulfonated β-lactam ring in a non-canonical, cysteine-containing thioesterase domain. This biosynthetic route is distinct from three other known tactics in Nature that generate β-lactam rings. These discoveries open the way to production of known and new monobactams by fermentation and semi-synthetic methods not previously available.
In a similar vein, the comparatively well-studied biosynthesis of the simplest carbapenem affords the possibility, using the known biosynthetic enzymes, to produce more structurally complex and therapeutically useful carbapenems ie Meropenem by a fermentation process. Carbapenem synthase (CarC) performs the last step of the biosynthesis of the simplest carbapenem through a remarkable two-step reaction consisting of an epimerization followed by desaturation. Several attempts were made to expand the substrate scope of CarC to accommodate structures that represent intermediates in the production of commercially available carbapenems
ChemInform Abstract: Chemical Synthesis of β‐Lactams: Asymmetric Catalysis and Other Recent Advances
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